ALZHEIMER DISEASE REDUCED CHOLINE PLASMALOGEN IN ALZHEIMER DISEASE BRAIN. Alzheimer disease (AD) is a progressive neurodegenerative disorder characterized by senile (neuritic) plaques containing amyloid and neurofibrillary tangles, neuroinflammation, synaptic loss and overexpression of arachidonic acid (AA, 20:4n-6) metabolizing enzymes. Disturbed brain lipid concentration changes have been reported, but partially or as percent of total. We measured absolute lipid concentrations (per gram wet weight) in postmortem prefrontal cortex from 10 AD patients and 9 controls. The major difference from control was a significant 73% decrease in plasmalogen choline. This reduction, suggesting extensive membrane remodeling and consistent with our prior report of a reduced critical temperature of AD lipids, may contribute to membrane instability and synaptic loss in AD (2) . BIOMARKERS AND EVOLUTION IN ALZHEIMER DISEASE. Brain regions with highly neuroplastic long axonal connections, which expanded rapidly during hominid evolution, are preferentially affected by Alzheimer disease (AD), and there is no natural animal model with full disease pathology (neurofibrillary tangles and neuritic amyloid plaques). Thus, it is possible that AD is uniquely human disease that was introduced during hominid evolution. This introduction may be related to increased neuroplasticity of vulnerable regions, and this neuroplasticity may be related to brain lipid metabolism. (8) ALTERED NEUROINFLAMMATORY, ARACHIDONIC ACID AND SYNAPTIC MARKERS IN ALZHEIMER DISEASE BRAIN. Our recent PET study demonstrated upregulated brain AA metabolism in AD patients, consistent with neuroinflammation. We directly confirmed neuroinflammatory changes associated with disturbed AA and docosahexaenoic acid (DHA, 22:4n-3) metabolism by studying postmortem frontal cortex from 10 AD patients and 10 age-matched controls. AD cortex showed significant increases in protein and mRNA levels of AA-selective cPLA2-IVA, secretory sPLA2-IIA, cyclooxygenase-1 and -2, membrane prostaglandin synthase-1 and lipoxygenase- 12 and -15, enzymes involved in AA metabolism. Calcium-independent DHA selective iPLA2-VIA and cytosolic PGE2 synthase were decreased. Inflammation markers, interleukin-1beta, tumor necrosis factor-alpha, glial fibrillary acidic protein and CD11b were increased, and synaptic markers synaptophysin and drebrin were decreased. Increased AA cascade and inflammatory markers, and synaptic loss, can be targeted in the treatment of AD. (7) . DISTURBED NEUROTRANSMITTER TRANSPORTER EXPRESSION IN ALZHEIMER DISEASE. An imbalance of neurotransmission has been proposed to cause behavioral symptoms in AD. We tested whether the imbalance involves changes in neurotransmitter reuptake by vesicular glutamate transporters (VGLUTs), excitatory amino acid transporters (EAATs), the vesicular acetylcholine transporter (VAChT), the serotonin reuptake transporter (SERT), or the dopamine reuptake transporter (DAT), using postmortem prefrontal cortex from 10 AD patients and 10 controls. Compared with controls, protein and mRNA levels of VGLUTs, EAAT1-3, VAChT, and SERT were reduced in AD. Expression of DAT and catechol O-methyltransferase was unchanged. Reduced VGLUTs and EAATs likely alter glutamate recycling, and reduced SERT could exacerbate depression. The reduced VAChT expression could contribute to the recognized cholinergic deficit in AD. Altered neurotransmitter transporters likely contribute to neurotransmission dysfunction in AD and are potential therapeutic targets (1) . EPIGENETIC MODIFICATIONS IN ALZHEIMER DISEASE AND BIPOLAR DISORDER FRONTAL CORTEX. AD and bipolar disorder (BD) are progressive brain disorders associated with neuroinflammation and upregulated AA metabolism. We showed that some of these changes are associated with epigenetic modifications of relevant genes, using 10 AD and 10 control frontal cortex tissue. AD and BD brains showed global DNA hypermethylation and histone H3 phosphorylation, associated with hypo- and hypermethylation of CpG islands in cyclooxygenase-2 and brain-derived neurotrophic factor (BDNF) promoter regions, respectively. Only the AD brain showed hyper- and hypomethylated CpG islands in promoter regions for cAMP response element-binding protein and nuclear transcription factor kappa B genes, respectively. Only the BD brain showed increased global histone H3 acetylation and hypermethylation of the promoter region for the drebrin-like protein gene. Many epigenetic changes were inversely related to changes in mRNA and protein levels. These epigenetic modifications involving neuroinflammatory, AA cascade and synaptic markers likely contribute to progression in AD and BD and identify new targets for drug development. (4) SYNAPTIC LOSS OCCURS WITH NEUROINFLAMMATION IN PROGRESSIVE BRAIN DISEASE. Our review of the literature revealed that neuroinflammation, in AD and other neurodegenerative, neuropsychiatric and viral diseases, usually is accompanied by reduced pre-synaptic synaptophysin and post-synaptic drebrin. These synaptic changes likely contribute to the cognitive decline and behavioral changes associated with these progressive illnesses (5). BIPOLAR DISORDER AND SCHIZOPHRENIA ALTERED ARACHIDONIC ACID CASCADE ENZYMES IN BIPOLAR DISORDER BRAIN. Mood stabilizers approved for treating bipolar disorder (BD), when given chronically to rats, decrease expression of markers of the brain AA metabolic cascade, and reduce excitotoxicity and neuroinflammation-induced upregulation of these markers. We confirmed that AA metabolic markers are upregulated in the BD cortex, partially explaining the efficacy of these drugs, by measuring them in postmortem frontal cortex from 10 BD patients and 10 age-matched controls. Protein and mRNA levels of AA-selective cytosolic phospholipase A2 (cPLA2) IVA, secretory sPLA2 IIA, cyclooxygenase (COX)-2, and membrane prostaglandin E synthase (mPGES) were elevated, whereas levels of COX-1 and cytosolic PGES (cPGES) were reduced relative to controls. These results may explain why mood stabilizers are clinically effective. An upregulated cascade should be considered a target for drug development and for neuroimaging in BD, as well as in AD, where we found similar changes (3). DYSREGULATED NEUROTRANSPORTERS IN BIPOLAR AND SCHIZOPHRENIC CORTEX. Dysregulated glutamate, serotonin and dopamine neurotransmission has been reported in BD and schizophrenia (SZ). We tested whether dysregulation involves alterations in excitatory amino acid transporters (EAATs), the serotonin reuptake transporter (SERT), or the dopamine reuptake transporter (DAT), using postmortem frontal cortex from BD, SZ and control subjects (10 each). Compared to control levels, protein and mRNA levels of EAAT1 were increased in cortex from both BD and SZ patients, EAAT2 protein and mRNA levels were decreased in BD, EAAT3 and EAAT 4 protein and mRNA levels were higher in SZ. DAT protein and mRNA levels were decreased in both BD and SZ cortices, but SERT was unchanged in either brain. These changes would alter glutamatergic and dopaminergic function in BD and SZ. (6)